Rassegne
The role of stress and psychiatric comorbidities as targets of
non-pharmacological therapeutic approaches for migraine
Ruolo dello stress e delle comorbidità psichiatriche come target degli approcci
terapeutici non farmacologici per l’emicrania
CORINNA PANCHERI
1, ANNALISA MARAONE
1, VALENTINA ROSELLI
1, MARTA ALTIERI
1,
VITTORIO DI PIERO
1, MASSIMO BIONDI
1, MASSIMO PASQUINI
1, LORENZO TARSITANI
1**E-mail: [email protected]
1Department of Human Neurosciences, Policlinico Umberto I, Sapienza University of Rome, Italy
IINTRODUCTION
People suffering from psychiatric disorders and emotion-al difficulties may turn to various providers to ask for help, especially mental health specialists1. In mental health
set-tings, psychotherapy is one of the main therapeutic options available for patients suffering from a variety of common and mild or moderate mental disorders. Psychological inter-ventions are the only indicated options for personality disor-ders. Also, psychotherapy is often offered to persons seeking help for emotional distress correlated with stressful somatic
conditions such as migraine. The scientific literature shows an association between migraine and several psychiatric con-ditions that may lead people to seek psychotherapeutic help, such as stress-related emotional difficulties, personality dis-orders, depressive and anxiety disdis-orders, bipolar spectrum disorders and sleep disorders2,3. Furthermore, many studies
developed hypotheses on the contribution of depression and anxiety to the chronification of migraine, increasing the in-terest in psychological integrative solutions4-7. This paper
aims at presenting the interconnections between psychiatric disorders and migraine with a specific focus on
pharma-SUMMARY. This narrative review addresses the interconnections among stress, mental disorders and migraine with a specific focus on
non-pharmacological interventions that may be effective in improving both migraine and the psychiatric comorbidity. Migraine is often comor-bid with depression, anxiety, personality disorders, and sleep disorders. Subjective stress and stressors are common triggers for migraine at-tacks and are risk factors for chronification, whilst mental disorders and stress responses are closely linked in a bidirectional relation. Recent studies show that psychiatric comorbidity is associated with migraine severity, worse outcomes, increased disability and reduce quality of life. Numerous studies on non-pharmacological interventions for migraine were published and behavioural treatments included biofeedback, cog-nitive-behavioural therapy, relaxation training, stress management and brief psychodynamic psychotherapy. Taken together, psychological in-terventions proved to be effective in migraine treatment and a combination of pharmacological and psychological treatment appear to be more effective than either medication or psychotherapy alone. Non-pharmacological interventions effectiveness should be due to the im-provement of migraine, stress-related vulnerability and mental disorders together and the combined treatment could prevent the chronifica-tion circuit of migraine. Well-designed long-term studies are needed to clarify comparative effectiveness of non-pharmacological techniques in the treatment and the prevention of migraine.
KEY WORDS: migraine, comorbidity, mental disorders, psychiatric disorders, psychotherapy.
RIASSUNTO. Lo scopo di questa revisione è quello di analizzare la correlazione tra stress, disturbi mentali ed emicrania, con un focus
spe-cifico sugli interventi non farmacologici, che possono essere efficaci nel migliorare sia l’emicrania sia la comorbilità psichiatrica. L’emicrania è stata spesso associata a depressione, ansia, disturbi della personalità e disturbi del sonno. Lo stress soggettivo e gli stressor sono elementi scatenanti comuni per gli attacchi di emicrania e, inoltre, sono fattori di rischio per la sua cronicizzazione, mentre i disturbi mentali e le ri-sposte allo stress sono strettamente collegati all’emicrania in una relazione bidirezionale. Studi recenti mostrano che la comorbilità psichia-trica è associata a una maggiore gravità dell’emicrania, a un peggiore outcome, all’aumento della disabilità e alla riduzione della qualità del-la vita. Gli interventi non farmacologici e i trattamenti comportamentali come il biofeedback, del-la terapia cognitivo-comportamentale, le tec-niche di rilassamento, la gestione dello stress e la psicoterapia psicodinamica breve si sono dimostrati efficaci nel trattamento dell’emicrania. Inoltre, la terapia combinata, farmacologica e non, sembra essere più efficace della sola farmacoterapia o psicoterapia. Gli interventi non far-macologici nei pazienti con emicrania sembrano favorire il miglioramento dei sintomi e la riduzione della vulnerabilità allo stress e ai disturbi mentali e, il trattamento combinato, potrebbe prevenire i meccanismo di cronicizzazione dell’emicrania. Sono necessari studi a lungo termi-ne per chiarire l’efficacia comparativa delle tecniche non farmacologiche termi-nel trattamento e termi-nella prevenziotermi-ne dell’emicrania.
cological interventions that may be effective in improving both migraine and the psychiatric comorbidity and to pre-vent the so called chronification circuit.
A non-systematic search was performed using MED-LINE/PubMed database with the following key words: (mi-graine OR headache) AND (depression OR anxiety OR per-sonality disorder); (migraine OR headache) AND (sleep problems OR sleep disorder); (migraine OR headache) AND psych* AND stress; (migraine OR headache) AND (psychological intervention OR psychological treatment OR non-pharmacological intervention OR psychotherapy). In the Table 1, inclusion criteria for papers selection are report-ed.
MIGRAINE AND PSYCHIATRIC COMORBIDITY
Approximately 12% of the general population suffers from migraine8 and about 9% of people suffering from
episodic migraine have chronic migraine9. Several studies
suggest that migraine is more than two times more frequent in women than in men10,11.Moreover, women have a greater
risk to develop disability12 as well as a greater risk of
evolu-tion from episodic to chronic migraine13.
The association between migraine and psychiatric disor-ders has been described in both clinical and community based populations. Many studies confirmed the presence of a high co-occurrence between depression, anxiety, personality disorders, sleep problems and migraine. Table 1 summarizes main studies on this comorbidity. Patients with migraine pre-sented with a significantly greater number of comorbid psy-chiatric disorders than patients without migraine14.
Epidemi-ologic studies also report a female tendency to development both depression and anxiety disorders in migraineurs with a prevalence twice in women than men15,16. Moreover some
studies demonstrated that psychiatric comorbidities are more prevalent in chronic migraine than in episodic mi-graine9,17-19.
The presence of a psychiatric comorbidity seems to en-hance migraine triggers susceptibility and the number of headaches/month20, as well as to increase disability and to
re-duce quality of life (QoL). Moreover, patients with comorbid mental disorders and migraine show a worse response to mi-graine treatment (due especially to low adherence), which can negatively modify long-term outcomes of migraineurs patients21,22.
Patients with migraine and a comorbid mental disorder have worse general health outcomes compared with individ-uals with one condition23,24.
Concerning depression, the nature of the relation with mi-graine is not clearly demonstrated, but longitudinal studies suggest a bi-directional relationship. Breslau and colleagues, in three longitudinal studies15,25,26, found similar figures for
new onset migraine in subjects with depression and for new onset depression in migraineurs. However, Swartz did not confirm the higher risk of new onset migraine in depressed patients27. A recent review and meta-analysis found that the
effects of migraine on depression was equal to OR=1.81 (95% CI=1.20-2.72) in cohort studies, and OR=2.00; 95% CI=1.64-2.43 in cross sectional studies, concluding that mi-graine can play an important role in increasing the incidence of depression in affected patients28.
Depression was also a significant predictor of onset of chronic migraine in patients with episodic migraine (OR=1.65, 95% CI=1.12-2.45) and the risk of chronic mi-graine onset increased with depression severity6,19.
Anxiety Disorders too seems to be strongly related to mi-graine (Table 1) and a factor potentially associated with re-duced perception of efficacy with acute treatment, long-term migraine persistence, headache-related disability and with chronic outcomes13,29,30.
Concerning Personality Disorders, recent studies suggest that migraineurs and chronic migraineurs have higher rates of certain personality disorders as compared to individuals without migraine31,32 (Table 1). The coexistence of a
border-line personality disorder seems associated with more perva-sive headache, more migraine-related disability, and an in-crease difficulty to treat due to a higher prevalence of med-ication overuse and more unscheduled visits for acute mi-graine treatment33,34. Although less investigated than
border-line personality disorder, avoidant personality disorder and obsessive-compulsive personality disorder, which are classi-fied in a different cluster of personality disorders, have also been associated with migraine and seem to negatively impact migraine treatment, contributing to medication overuse and poorer prognosis35,36. However, literature is scarce and a
cause-effect relationship between personality disorders and migraine remains unproven.
Sleep problems are more prevalent in patients with mi-graine than in the general population37. The association
be-tween severe sleep disturbances and migraine seems to be more pronounced for chronic migraine38. Patients with
chronic migraine reported shorter nightly sleep times than those with episodic migraine, and were more likely to exhib-it trouble falling asleep, staying asleep and sleep triggering headache39. As with depression and anxiety, also for sleep
disturbances the relationship with migraines appear bidirec-tional with pain negatively impacting sleep and vice versa40.
ROLE OF THE STRESS AND THE CHRONIFICATION CIRCUIT
Stress is the factor listed most often by migraine sufferers as a trigger for their attacks. Some studies show that 50% to 80% of patients report stress as a trigger factor for their mi-graine attacks. It has been suggested that acute stress can provoke biological modifications lowering the threshold of susceptibility to a migraine attack41. Moreover, when
behav-ioural or physiological stressors are frequent and/or severe, allostatic responses can become dysregulated and maladap-tive (“allostatic load”), altering the normal response of phys-iological systems and leading to alterations in brain net-works, both functionally and structurally. These effects can lead to abnormal responses to environmental conditions and to the chronification of the disease42,43. The overuse of
anal-gesic medications, might affect allostasis, too44. Moreover, it
has been well established from the 1970s that stress and psy-chiatric disorders are extremely related with a bidirectional relationship45. Therefore, migraine, stress and psychiatric
dis-orders seem to be tied together, leading patients into a chronification circuit where every condition may provoke or incentivize the other with a final reduction in quality of life and worse outcomes.
Table 1. Principals studies on the prevalence of depressive, anxiety and personality disorders in patients affected by migraine. (Author, year)reference Psychiatric diagnosis Sample Psychiatric comorbidity Results/conclusions Depressive and/or anxiety disorders
(Merikangas, 1990)79 PI N=457 Depression OR (95% CI): 2.2 (1.1-4.8);
Concluded a higher risk of depression and anxiety and depressive disorders in combination.
(Breslau, 1994)25 PI N=1007 Depression OR (95% CI): - New-onset migraine 3.5 (2.2-5.6) - New-onset depression 3.6 (2.6-5.2)
Data strongly support clinical observations on migraine-major depression comorbidity. (Verri, 1998)80 PI DSM-III N=88 MDD: 25% GAD: 69.3%
Concluded high comorbidity of anxiety and mood disorders in migraineurs.
(Mitsikostas, 1999)81 HAM-A and D N=620
(170 with migraine)
Depressive Disorders OR 7.3 (prevalence 4%)
Higher scores of anxiety and depression in migraineurs compared to healthy controls. (Breslau, 2000)15 PI DSM-IV N=1287 (536 with migraine) Depression OR (95% CI): 3.5 (2.6-4.6). - New-onset migraine 2.8, 2.2 to 3.5 - New-onset depression 2.4, 1.8 to 3.0
Different causes may underlie the co-occurrence of major depression in persons with migraine compared with persons with other severe headaches. (Juang, 2000)82 MINI N=261 (152 with migraine) Depressive Disorders: 46% Anxiety Disorders: 28% Psychiatric comorbidity, especially MDD and panic disorders, was highly prevalent in patients with migraine. (Swartz, 2000)27 PI DSM-III N=1343 (118 with migraine) Depression comorbidity OR (95% CI): 3.1, (2.0-4.4) New-onset migraine in depression 0.68 (.02-2.0)
There is a strong cross-sectional relation between depression and migraine, but no
association between antecedent depression and incident migraine. (McWilliams, 2004)84 PI DSM-III N=3032 (340 with migraine) Depression OR (95% CI): 2.8 (2.2-3.7)
Panic attacks OR (95% CI): 3.6 (2.6-3.0)
GAD OR (95% CI): 3.9 (2.5-6)
Strong association between psychiatric disorders and migraine. Association was stronger for anxiety disorders than depression. (Atasoy, 2005)35 PI SCID-CV N=117 (58 with migraine) Depressive Disorders: 36% Anxiety Disorders: 17% (GAD: 8.6%, Panic 6.9%)
High comorbidity of anxiety and depressive disorders in patients with migraine. (Senaratne, 2010)14 SCID DSM-IV N=206 (138 with migraine) Anxiety Disorders: 67% comorbidity with: - MDD/Dysthymia: p=0.008 - GAD/PD: p=0.048
The prevalence of migraine was significantly higher in patients with a diagnosis of PD or MDD/dysthymia compared to other psychiatric disorders. (Goulart, 2014)85 CIS-R N=11792
(1261 with migraine)
For daily headaches: MDD OR (95% CI): 6.94 (4.20-11.49) GAD OR (95% CI): 4.0 (2.6-7.0) PD OR (95% CI): 2.1 (0.6-7.1) Mixed anxiety-depressive disorder OR (95% CI): 1.9 (1.1-3.0)
The increase in migraine frequency was associated with progressively higher frequencies of having mood/anxiety disorders. (Fuller-Thomson, 2017)86 WHO-CIDI N=21502 (2232 with migraine) GAD OR (95% CI): 2.46 (2.0-3.0)
GAD is robustly associated with migraine.
NON-PHARMACOLOGICAL INTERVENTIONS
Due to the high prevalence of psychiatric comorbidity and stress in migraine and the impact of comorbidity on out-comes, in the last decades attention was directed to psycho-logical interventions aimed at addressing both migraine and mental conditions. Following the history of psychosomatic medicine started a century ago46, from the ’80s studies on
psychological treatment of headache and migraine were published and included biofeedback, cognitive-behavioural therapy (CBT), relaxation training, stress management and other techniques47. These behavioural therapies have very
well-established efficacy for treatment of migraine, as
con-firmed in numerous studies and meta-analyses48.
Further-more, the combination of pharmacological treatment and behavioural therapy has been found to be more effective than either medication or behavioural therapy alone49-51.
CBT is an important treatment component especially for patients with a comorbid psychiatric conditions52. The
ra-tionale for the use of CBT in migraine management derives from the observation that the way people cope with every-day stressors can precipitate, exacerbate, or maintain headaches and increase headache-related disability and dis-tress.
Advice to identify and avoid triggers, particularly those re-lated to pathological mental conditions (stress and negative
(Continued) - Table 1
(Author, year)reference Psychiatric diagnosis Sample Psychiatric comorbidity Results/conclusions Depressive and/or anxiety disorders
(Dindo, 2017)87 PI DSM-IV TR N=227 (31 with mi-graine) MDD OR (95% CI): 3.4 (1.1-10.2) GAD OR (95% CI): 3.0 (1.3-6.8) A diagnosis of MDD or GAD was associated with significantly increased risk of having migraine. Personality disorders Personality disorders
(Wang, 2005)36 DAPP N=160 (48 with migraine)
Personality traits (migraineurs vs controls p<0.5):
- Submissiveness - Cognitive distortion - Social Avoidence - Self-Harm
Results suggests that mi-graine is comorbid with borderline personality traits, and avoidant per-sonality traits. (Lake, 2009)88 PI DSM-IV TR N=267 (226 with CM) Personality Disorders: 26% - Cluster B: 16% - Cluster C: 12%
Most common personality disorders of which migraineurs are affected are from cluster B and cluster C. (Manlik, 2012)89 SIDP DSM-III N=352 (49 with mi-graine) Personality Disorders OR (95% CI): 3.44 (1.8-6.7) - Passive-aggressive OR (95% CI): 3.18 (1.3-7.8) - Mixed OR (95% CI): 5 (1.5-16.6)
The most notable findings are the association of migraine with passive-aggressive and mixed personality disorders (DSM-III)
(Kayhan, 2016)32 SCID-II N=205 (105 with CM)
Any Personality Disorders 81% OR (95% CI) 0.05 (0.02-0.11)
Most prevalent disorders were Obsessive-compulsive (50.5%), avoidant (19%), dependent (19%), passive-aggressive (13.3%), narcissistic (6.7%), borderline (5.7%), histrionic (5.7%) disorders.
Legend: PI=Psychiatric Interview; HAM-A and D=Hamilton Rating Scale for Anxiety and Depression MDD=Major Depressive Disorder; GAD=Generalized Anxiety Disorder; MINI=Mini-International Neuropsychiatric Interview; HADS=Hospital Anxiety and Depression Scale; CIS-R=Clinical Interview Schedule-Revised; WHO-CIDI=World Health Organization Composite International Diagnostic Interview; PD=Panic Disorder; DAPP=Dimensional Assessment of Personality Pathology.; SCID-II=Structured Clinical Interview for DSM IV-TR.
emotions, anger, lack of sleep or excess of sleep, alcohol abuse etc.)53 as a good means of preventing headaches, has been
standard practice for decades. Martin and colleagues recently developed an alternative approach to trigger management called “learning to cope with triggers” (LCT)54 consisting in a
graduated exposure to selected triggers to promote desensiti-zation. They propose an integrative CBT/LCT approach which aims to enhance the effectiveness of CBT in mi-graineurs55. The same Authors in a randomized controlled
tri-al in patients with comorbid headaches and depression, found that the CBT group improved significantly more than the con-trol group mostly in men than women56. Indeed, the latest
out-come is in contrast with literature57 and it could be associated
with a greater tendence to ruminate in females than males58.
This ruminative response style may increase the risk to devel-op a persistence depression59 and this could explaine the
gen-der difference in treatment response56. Improvements
achieved with treatment were maintained at four month fol-low-up. Furthermore, advice to avoid triggers altogether may lead to reduced internal locus of control for headaches, with attendant adverse effects on self-efficacy, particularly con-cerning perceived capacity to cope effectively with triggers60.
The self-management model, typically employed in cogni-tive-behavioural interventions, is very useful in patients with migraine and comorbid psychiatric disorders. This model op-timizes medication adherence, effects lifestyle changes, im-proves functioning, limits disability, teaches way to manage stress and affective distress as well as educates about the role of cognitions and behaviours in health and illness61.
In recent studies, different forms of CBT in migraineur patients, have shown to be effective not only to manage pa-tients’ headache pain, but also on reducing the depressed mood and/or the anxiety symptoms62-64. Also the
biofeed-back treatment proved to be effective both on migraine and anxiety and depressive comorbidity65,66. A recent pilot
ran-domized controlled trial showed that biofeedback added to traditional pharmacological therapy in the treatment of medication overuse headache improved outcome in headache frequency, amount of drug intake and active cop-ing with pain, also after 4 months of follow-up67. Though
more research is needed on the effects of treating comorbid psychiatric disorders on headache outcomes and vice versa, these findings help to demonstrate the bidirectional rela-tionship between depression, anxiety and migraine.
Other “emerging therapies” include: acceptance and com-mitment therapy (ACT)68,69, mindfulness-based
interven-tion70-72, and behavioural interventions that target comorbid
conditions as sleep disturbances73,74. Though existing studies
are small, these approaches have produced positive out-comes, particularly in the domains of improving headache-related functioning and affective distress75. There is evidence
that relaxation techniques, particularly progressive muscle relaxation, and different biofeedback techniques are effec-tive in reducing frequency and severity of migraine76.
In a study on patients with medication overuse headaches, short-term psychodynamic psychotherapy added to pharma-cological therapy, at 12-month follow-up, was associated with decreased headache frequency and medication intake, a low-er relapse rate, and a lowlow-er risk of developing chronic mi-graine, as compare to pharmacotherapy alone77. Less
stud-ied, brief psychodynamic treatments appear promising in terms of feasibility compared to standard psychodynamic
therapy. Insight oriented approaches could be helpful in de-creasing stress-related vulnerability as well as somatization tendencies, potentially leading to long term results. Future studies are needed to demonstrate this hypothesis.
Importantly, all psychological interventions used in mi-graine proved to be effective in anxiety, depressive and stress-related disorders alone. Hence, the effect in patients with migraine and psychiatric comorbidity should be due to the improvement of migraine, stress-reactions and mental disorders together. In theory, the psychological effect of treatments could also prevent the chronification circuit ad-dressing all conditions involved.
Finally, it is useful to note that the use of psychological techniques in migraineurs with comorbid mental disorders may provide a nonthreatening way to introduce the patient to the process of psychological treatment and thus, to en-courage the patient to acknowledge psychological difficulties and accept treatment for psychiatric disorders61.
From a mental health perspective, non-pharmacological in-terventions for mental disorders in children and adolescents are highly indicated to improve long-term outcomes and avoid chronicity. However, most studies on migraine with psychiatric comorbidity are on adults. Only 11 trials from 2010 assessed behavioural approaches, mostly CBT, in adolescents or young adults with headache78. Two studies involved only patients
with chronic migraine and depression or anxiety were consid-ered as a secondary outcome in 4 studies. Non-pharmacologi-cal treatments were shown to produce sizeable effects on headache frequency and marked improvements were noted in depressive and anxiety symptoms. Future well-designed stud-ies are necessary to explore the short- and long-term effec-tiveness of behavioural intervention in adolescents or young adults with migraine and psychiatric comorbidity.
CONCLUSIONS
Comorbid mental disorders, specially anxiety, depressive, and personality disorders are the rule rather than the exception in migraine. Stress-related vulnerability is associated with both migraine and psychiatric conditions. The co-occurrence of these conditions has a great impact on health. Psychological in-terventions are clearly indicated and effective for mild/moder-ate mental disorders and stress vulnerability. Several studies showed their effectiveness in patients with migraine, usually added to pharmacological treatment, suggesting a combined action on psychological and somatic symptoms. Future re-search is needed to better understand long-term effectiveness and to compare different psychological techniques.
Conflict of interests: the authors have no conflict of interests to declare.
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